The pathology and biology of experimentally induced and naturally occurring neoplasms of rodents are characterized and compared using serial sacrifice studies, avidin-biotin (ABC) immunocytochemistry, automated image analysis with stereology, conventional light microscopy, ultrastructure and histochemistry. Histopathogenesis investigations were performed for mouse and hamster liver, mouse and rat lung, and sarcomas induced by Harvey sarcoma virus. Ras-Ha p21 was found by ABC immunocytochemistry to be present on the cell membranes of sarcoma cells, erythroblasts and reticulum cells in viral infected mice but not in other normal cells using a sheep IgG to a peptide in p21. Using this antiserum we could not demonstrate immunoreactive p21 in any other tumors, spontaneous or induced, even some chemically-induced tumors with demonstrably transfectable Ha-Ras. The vast majority of early or late pulmonary tumors in rats and mice were immunoreactive for the apoproteins of pulmonary surfactant but never Clara cell antigen. This finding suggested that the alveolar Type II cell is the origin of lung tumors of rats and mice. Some lung tumors of mice induced by ethylnitrosourea demonstrated no reactive antigens. The phenotype of mouse liver tumors initiated and/or promoted by chemicals was found to depend on the promoters. For example, di(2-ethylhexyl)phthalate promoted basophilic tumors while phenobarbital and diazepam promoted eosinophilic tumors.